Stimulant abuse (including both cocaine and amphetamines) is a serious public health problem. There are thought to be over 3 million current users of these drugs in the United States, and these drugs account for numerous emergency room visits each year. Abuse of these drugs is associated with a high rate of relapse. Despite significant unmet medical need no pharmacotherapies are currently approved for the treatment of stimulant abuse. Several programs aimed at using replacement therapy have shown some promise. Recently, there have also been reports showing kappa-opioid receptor antagonists can modulate stress responses, and stress response and depression have been shown to be important triggers for relapse. For this reason kappa-selective opioid receptor agonists and antagonists have gained some attention as potential treatments for stimulant abuse. The pawhuskins are a small set of prenylated stilbenes reported from a North American prairie plant in 2004. They were shown to have some opioid receptor modulating function in this early report. This early career award in the basic chemistry of drug abuse prevention is designed to test the hypothesis that drugs for the treatment of stimulant abuse can be derived from the pawhuskins. We propose three specific aims that are designed to test this hypothesis by systematically modifying the pawhuskin scaffold. We will first probe the requirements for hydrogen bond donors present in the natural products by blocking groups. We will then synthesize a series of analogs designed to enhance specific opioid receptor binding to improve the affinity and receptor subtype selectivity of the pawhuskin core. PUBLIC HEALTH RELEVANCE: Stimulant abuse is a major public health problem in the United States with cocaine and methamphetamine being the primary drugs of abuse in this category. Abuse of these drugs is associated with long lasting behavioral changes and propensity for relapse. Despite the morbidity and mortality associated with stimulant abuse no pharmacotherapies are currently approved for treatment of this disease. Novel therapeutics that could help with the relapse effect or otherwise improve treatment outcomes should be of high priority.